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Published on: May 27, 2021
PARP inhibitors in oncology: a new synthetic lethal approach to cancer therapy
V Kruse1, S Rottey, O De Backer
1Department of Medical Oncology, Ghent University Hospital, Belgium. Vibeke.Kruse@uzgent.be
Abstract:
Damage to DNA has emerged as a major culprit in cancer. Mammalian cells are continuously exposed to DNA damage, caused by exogenous toxins as well as endogenous activities such as DNA replication and cellular free radical generation. It is therefore essential that cells have DNA repair mechanisms in place to preserve its genomic integrity. Interestingly, cancer cells frequently harbour defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis, but also provides a weakness in the tumour that can be exploited therapeutically. In this context, it has been shown that homologous recombination (HR)-deficient tumour cells--including those with defects in BRCA1/2--are highly sensitive to blockade of the base excision repair (BER) pathway via inhibition of the poly (ADP-ribose) polymerase (PARP) enzyme. This provides the basis for a novel 'synthetic lethal' approach to cancer therapy. Recent clinical trials have shown an enhancement of the cytotoxic effect of chemotherapy by adding a PARP inhibitor to the standard treatment. Still, clinical outcome may be even further improved if these drugs would be used as first-line therapy. In conclusion, it can be stated that an exciting new class of drugs has entered the arena of cancer therapy. However, additional clinical studies are needed before PARP inhibitors can definitely enter daily clinical practice.
Insights
DNA damage is a key factor in cancer. Targeting DNA repair pathways, like base excision repair (BER) with poly (ADP-ribose) polymerase (PARP) inhibitors, offers a novel synthetic lethal cancer therapy. Further studies are needed for clinical integration.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA damage is a significant factor in cancer development.
- Cancer cells often have defects in DNA repair pathways, leading to genomic instability.
- This genomic instability can be exploited for therapeutic strategies.
Purpose of the Study:
- To explore the therapeutic potential of targeting DNA repair pathways in cancer.
- To investigate the efficacy of poly (ADP-ribose) polymerase (PARP) inhibitors in combination with chemotherapy.
- To evaluate PARP inhibitors as a potential first-line cancer therapy.
Main Methods:
- Investigating the sensitivity of homologous recombination (HR)-deficient tumor cells to base excision repair (BER) pathway blockade.
- Analyzing data from recent clinical trials involving PARP inhibitors and chemotherapy.
- Assessing the potential of PARP inhibitors as a first-line treatment strategy.
Main Results:
- Homologous recombination (HR)-deficient tumor cells, including those with BRCA1/2 defects, show high sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition.
- Clinical trials indicate that adding PARP inhibitors enhances the cytotoxic effects of chemotherapy.
- PARP inhibitors represent a promising new class of cancer therapeutics.
Conclusions:
- A novel 'synthetic lethal' approach targeting DNA repair defects in cancer is effective.
- PARP inhibitors show potential for improving cancer treatment outcomes when combined with chemotherapy.
- Further clinical studies are required to establish PARP inhibitors in routine clinical practice.
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